Local Anesthetic Cardiotoxicity: Nanotechnology Therapy

局部麻醉心脏毒性：纳米技术治疗

• 批准号: 6743187
• 负责人: DONN MICHAEL DENNIS
• 金额: $ 25.58万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743187
• 关键词: adsorption; anesthesia complication; cardiac myocytes; cardiotoxin; clinical research; detoxification; drug adverse effect; electrocardiography; electron spin resonance spectroscopy; electrophysiology; guinea pigs; heart ventricle; high performance liquid chromatography; human tissue; infrared spectrometry; local anesthesia; nanotechnology; ultraviolet spectrometry

DESCRIPTION (provided by applicant): Local anesthetics (LAs) reversibly prevent impulse transmission in nerves by voltage-, time- and frequency-dependent blockade of sodium channel conductance (I-Na). These pharmacological actions underlie the therapeutic use of LAs in clinical care to provide regional anesthesia (e.g., epidural blockade) for patients undergoing surgical procedures or childbirth. However, inadvertent intravascular injection or overdose may lead to undesired INa blockade in other tissues (e.g., heart, central nervous system) and thereby cause potentially life threatening adverse events (e.g., cardiac arrest, seizures). Although seizure activity and respiratory depression caused by LA overdose are potentially life threatening, these events can be readily treated with antiepileptic medications and controlled artificial ventilation, respectively. Of equal or greater importance, few options (e.g., ACLS) currently exist for treatment of cardiac toxicity caused by intravascular injection. For these reasons, an agent or technique allowing rapid, efficacious treatment of the cardiac effects of LA toxicity would be useful. The objectives of this grant are to generate the knowledge necessary to create agents specifically designed to treat patients suffering from the toxic effects of LAs. Recent advances in particle science engineering now afford new and exciting opportunities to develop highly effective therapeutic strategies aimed at successfully treating drug poisonings. Specifically, the recent advent of nanotechnology with its tremendous potential to solve major biomedical problems now offers unparalleled opportunities to solve the problem of LA toxicity. Four types of biocompatible and biodegradable nanoparticles (NPs) with 10-100 nm diameter will be synthesized by colleagues in the NSF Engineering Research Center for Particle Science and Technology for detoxification of LAs. These NPs will rely on absorption (microemulsions), adsorption (electron acceptor), or both mechanisms (2 types of "smart" microemulsions) to reduce the free concentration of LA in various media and decrease the biological effects of LA in tissues and intact organisms. The NPs will be studied to 1) detail the physicochemical characterization of the NP-LA interaction (Objective A), and 2) determine whether the cardiotoxic effects of LAs can be attenuated by NPs in biological systems (Objective B). This highly multidisciplinary project spanning organic chemistry, engineering, and medicine contains two objectives and three specific aims: Specific Aim #1: Determine the extraction efficiency of NPs to remove LAs from simple (normal saline) and complex (human plasma and blood) media. Optimize LA extraction efficiency of the various NPs. Specific Aim #2: Determine the molecular mechanisms whereby the different types of NPs can efficiently extract LAs. Specific Aim #3: Determine the effectiveness of nanoparticles to attenuate or reverse the cardiotoxic effects of LAs at three functional levels: 1) single cell (ventricular myocytes), 2) tissue (isolated hearts), and 3) intact rat (closed chest).

描述（由申请人提供）：局部麻醉剂（LA）通过电压、时间和频率依赖的钠通道电导（I-Na）阻断来可逆地防止神经中的冲动传递。这些药理作用是局麻药在临床护理中的治疗用途的基础，为接受外科手术或分娩的患者提供区域麻醉（例如硬膜外阻滞）。然而，无意的血管内注射或过量可能会导致其他组织（例如心脏、中枢神经系统）出现不希望的 INa 阻断，从而导致潜在危及生命的不良事件（例如心脏骤停、癫痫发作）。尽管 LA 过量引起的癫痫发作和呼吸抑制可能危及生命，但这些事件可以分别通过抗癫痫药物和受控人工通气轻松治疗。同样或更重要的是，目前治疗血管内注射引起的心脏毒性的选择（例如 ACLS）很少。由于这些原因，能够快速、有效地治疗局麻药毒性对心脏的影响的药剂或技术将是有用的。这笔赠款的目的是产生必要的知识，以创造专门设计用于治疗遭受局麻药毒性作用的患者的药物。粒子科学工程的最新进展现在提供了新的、令人兴奋的机会来开发旨在成功治疗药物中毒的高效治疗策略。具体来说，最近出现的纳米技术具有解决重大生物医学问题的巨大潜力，现在为解决 LA 毒性问题提供了无与伦比的机会。 NSF 粒子科学与技术工程研究中心的同事将合成四种直径为 10-100 nm 的生物相容性和可生物降解的纳米颗粒 (NP)，用于 LA 的解毒。这些纳米粒子将依靠吸收（微乳液）、吸附（电子受体）或两种机制（两种类型的“智能”微乳液）来降低各种介质中 LA 的游离浓度，并降低 LA 在组织和完整生物体中的生物效应。研究 NP 的目的是 1) 详细描述 NP-LA 相互作用的物理化学特征（目标 A），2) 确定生物系统中的 NP 是否可以减弱 LA 的心脏毒性作用（目标 B）。这个跨有机化学、工程和医学的高度多学科项目包含两个目标和三个具体目标： 具体目标#1：确定 NP 的提取效率，以从简单（生理盐水）和复杂（人血浆和血液）介质中去除 LA。优化各种 NP 的 LA 提取效率。具体目标#2：确定不同类型的 NP 可以有效提取 LA 的分子机制。具体目标#3：确定纳米颗粒在三个功能水平上减弱或逆转 LA 的心脏毒性作用的有效性：1) 单细胞（心室肌细胞）、2）组织（离体心脏）和 3）完整大鼠（闭合胸腔）。